Effector Pathways of Natural Killer Cells

Cell-mediated cytotoxicity is an important mechanism of tumor control (Melief 1992) and virus elimination (Zinkemagel and Rosenthal 1981) in vivo. Depending on the tumor target, the host has two complementary cytotoxic mechanisms at its disposal: cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. NK cells are not antigen specific in the classical sense and can be activated within hours without specific priming. In contrast, CTLs are induced by specific peptides presented by major histocompatibility complex (MHC) class I molecules, are antigen-specific, and act efficiently as effector cells only after an induction and proliferation phase of 5–8 days. A tumor or an infected cell can prime acquired immunity if it presents tumor-specific peptides in the context of MHC class I and/or class II molecules to CD8+ or CD4+ T cells, respectively (Melief 1992; van Pel et al. 1995). Under selective pressure, however, tumors may escape immune surveillance by variants that lack MHC class I and/or II molecules (Schrier et al. 1983; Smith et al. 1989; Uyttenhove et al. 1983), and some of these tumors have been shown to be controlled efficiently by NK cells in vivo (Karre et al. 1986, 1995). In addition, some viruses have been shown to use similar strategies to avoid immunological control: herpes simplex virus types 1 and 2 (Hill et al. 1994) and murine cytomegalovirus (del Val et al. 1992) downregulate MHC class I molecules upon infection, leaving only NK cells as effectors of cell-mediated cytotoxicity.